The major goal of cancer chemotherapy is the development of anti-cancer drugs that are effective in a wide range of cancers and produce no toxic effects in normal tissues. The target of such drugs should be expressed only in tumour cells and not normal cells. However, to date, no such tumour specific target, general to all types of cancers, has been identified.
The cytochromes P450 are a multi-gene family of constitutive and inducible enzymes, which have a central role in the oxidative metabolic activation and detoxification of both a wide range of xenobiotics (2-4) and several groups of endogenous compounds active in cell regulation and cell signalling including arachidonic acid (5), steroid hormones (6) and fatty acids (7). The major families of P450 involved in xenobiotic metabolism each consist of several individual forms with different regulatory mechanisms and substrate specificities (2). The majority of P450s are primarily expressed in liver (2) although individual P450 forms are also expressed in specific extra-hepatic tissues (8) including small intestine, kidney and lung.
The human CYP1 gene family (individual P450 forms are identified by the prefix CYP in accordance with the current P450 nomenclature (3)), which is one of the major P450 families involved in the metabolism of xenobiotics, is now known to consist of three individual forms classified into two sub-families. The CYP1A subfamily contains two highly homologous and well characterised but distinct members. CYP1A1 (9) and CYP1A2 (10). CYP1A1 is an inducible P450 expressed primarily in extraheptic tissues (11) while CYP1A2 is a major form of P450 that is constitutively expressed in liver (12). Recently a second human CYP1 subfamily has been identified which to date contains one member, CYP1B1 (1). This P450 is dioxin-inducible, and sequence analysis of CYP1B1 shows 40% homology with both CYP1A1 and CYP1A2. Although CYP1B1 is assigned to the CYP1 family on the basis of its sequence, it appears to be structurally distinct from both CYP1A1 and CYP1A2.
Several forms of P450 are considered to have an important role in tumour development since they can metabolise many potential carcinogens and mutagens (13). Moreover, P450 activity may influence the response of established tumours to anti-cancer drugs; several cancer chemotherapeutic agents can be either activated or detoxified by this enzymes system (14). The presence of individual forms of P450 had previously been investigated in different types of cancer including breast cancer (15), lung cancer (16), colon cancer (17) and head and neck cancer (18) to determine if intra-tumour metabolism of anti-cancer agents by P450 could occur and thus influence the response of tumours to these agents. These studies have generally shown that the level of the P450 forms investigated is significantly reduced or absent in tumours when compared with the adjacent normal tissue in which the tumours have developed. However, our recent studies of several different types of cancer (19) including breast cancer, oesophageal cancer and soft tissue sarcomas have shown that there may be tumour-specific expression of a CYP1 form of P450.
Although CYP1B1 mRNA had previously been identified by Northern blotting in several normal human tissues (1), the presence CYP1B1 protein itself had not been demonstrated.